Protein structural transitions critically transform the network connectivity and viscoelasticity of RNA-binding protein condensates but RNA can prevent it.

Autor: Tejedor AR; Department of Chemical Engineering, Universidad Politécnica de Madrid, José Gutiérrez Abascal 2, 28006, Madrid, Spain.; Maxwell Centre, Cavendish Laboratory, Department of Physics, University of Cambridge, J J Thomson Avenue, Cambridge, CB3 0HE, UK., Sanchez-Burgos I; Maxwell Centre, Cavendish Laboratory, Department of Physics, University of Cambridge, J J Thomson Avenue, Cambridge, CB3 0HE, UK., Estevez-Espinosa M; Maxwell Centre, Cavendish Laboratory, Department of Physics, University of Cambridge, J J Thomson Avenue, Cambridge, CB3 0HE, UK.; Department of Biochemistry, University College London, Gower Street, London, WC1E 6BT, UK., Garaizar A; Maxwell Centre, Cavendish Laboratory, Department of Physics, University of Cambridge, J J Thomson Avenue, Cambridge, CB3 0HE, UK., Collepardo-Guevara R; Maxwell Centre, Cavendish Laboratory, Department of Physics, University of Cambridge, J J Thomson Avenue, Cambridge, CB3 0HE, UK.; Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.; Department of Genetics, University of Cambridge, Cambridge, CB2 3EH, UK., Ramirez J; Department of Chemical Engineering, Universidad Politécnica de Madrid, José Gutiérrez Abascal 2, 28006, Madrid, Spain. jorge.ramirez@upm.es., Espinosa JR; Maxwell Centre, Cavendish Laboratory, Department of Physics, University of Cambridge, J J Thomson Avenue, Cambridge, CB3 0HE, UK. jr752@cam.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Sep 29; Vol. 13 (1), pp. 5717. Date of Electronic Publication: 2022 Sep 29.
DOI: 10.1038/s41467-022-32874-0
Abstrakt: Biomolecular condensates, some of which are liquid-like during health, can age over time becoming gel-like pathological systems. One potential source of loss of liquid-like properties during ageing of RNA-binding protein condensates is the progressive formation of inter-protein β-sheets. To bridge microscopic understanding between accumulation of inter-protein β-sheets over time and the modulation of FUS and hnRNPA1 condensate viscoelasticity, we develop a multiscale simulation approach. Our method integrates atomistic simulations with sequence-dependent coarse-grained modelling of condensates that exhibit accumulation of inter-protein β-sheets over time. We reveal that inter-protein β-sheets notably increase condensate viscosity but does not transform the phase diagrams. Strikingly, the network of molecular connections within condensates is drastically altered, culminating in gelation when the network of strong β-sheets fully percolates. However, high concentrations of RNA decelerate the emergence of inter-protein β-sheets. Our study uncovers molecular and kinetic factors explaining how the accumulation of inter-protein β-sheets can trigger liquid-to-solid transitions in condensates, and suggests a potential mechanism to slow such transitions down.
(© 2022. The Author(s).)
Databáze: MEDLINE
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